Project Summary There is a vital need to understand the causes of depression in order to develop effective treatments for the 11% of Americans who currently suffer from this debilitating disease. This project focuses on a new target, T helper 17 (Th17) cells, which we recently linked to depression susceptibility in mouse models and for which we identified feasible interventions. The overall objectives of this project are to identify characterize, localize and identify mechanisms of action of Th17 cells after stress and test the potential therapeutic impact of targeting Th17 cells to decrease vulnerability to depression, assessed by measuring depression-like behaviors in mice. This research evolved from the now well-established link between inflammation and depression. We reasoned that therapeutically targeting downstream, and prolonged, outcomes of inflammation may be more feasible than attempting to neutralize the multitude of cytokines that are transiently induced in the inflammatory response to stress. Inflammatory cytokines associated with depression drive the production of Th17 cells, and Th17 cells are already well- established to be toxic to the CNS. In mouse models, we found that Th17 cells are able to infiltrate mouse brain parenchyma after stress, these infiltrating cells exhibited characteristics of pathogenic (CCR6+ and IL-23R+) and follicular (CXCR5+) Th17 cells, and the presence of CCR6 on Th17 cells was required for them to promote learned helplessness. We also identified the gut as a likely source of infiltrating Th17 cells, as mice receiving CD4 cells from transgenic mice that express T cell receptor (TCR) specific for Segmented Filamentous Bacterium are sufficient to promote learned helplessness, whereas CD4 cells from wild-type mice are not. However, the mechanisms of action of Th17 cells in depression remain unclear. In this project, Specific Aim 1 will determine the characteristics of Th17 cells that promote depressive-like behaviors. We will identify factors associated with Th17 cell localization in the brain after stress. Specific Aim 2 will will determine the actions of Th17 cells in the brain that promote depressive-like behaviors. Using depleting approaches, we will identify the downstream cell effectors of Th17 cells responsible for depressive-like behaviors. Specific Aim 3 will determine if Th17 cells can be targeted to induce antidepressant effects. We will test if blocking Th17 cells using nanoparticles and engineered bacteria is sufficient to induce antidepressant actions. Altogether this project will identify the localization, the source, the characteristics and the mechanisms of action of Th17 cells in depressive-like behaviors and determine targeted strategy by which Th17 cell production following stress can be blocked in order to develop a new therapeutic strategy for depression, a prevalent, debilitating, and inadequately treated disease.